Delayed puberty: analysis of a large case series from an academic center

Despite the clinical importance of delayed puberty, the understanding of this condition is hampered by the lack of studies evaluating etiologies and predisposing factors among large case series. We performed a retrospective study of clinical and laboratory data from adolescents (< or =18 yr of age) with delayed puberty who had been seen in our clinic between 1/96 and 7/99 (n = 232 subjects; 158 males and 74 females). Family histories of pubertal timing among primary relatives were classified as negative, having at least a tendency to pubertal delay (development > or =1 SD beyond the mean), or diagnostic of delay (development > or =2 SD beyond the mean). The most common cause of delayed puberty was constitutional delay of growth and maturation (CD), which affected 53% of the subjects (63% of males and 30% of females). The remaining subjects could be divided into four categories: those with an underlying condition associated with delayed, but spontaneous, pubertal development [functional hypogonadotropic hypogonadism (FHH)], 19% of subjects; those with permanent hypogonadotropic hypogonadism, 12% of subjects; those with permanent hypergonadotropic hypogonadism, 13% of subjects; and those without clearly classified disorders, 3% of subjects. Like CD, FHH was male predominant, whereas the other categories either affected both genders equally or were predominantly female. In total, 50 different etiologies led to pubertal delay within our case series. Data permitted classification of family histories of pubertal timing among primary relatives in 95 of 122 of the CD and in 25 of 45 of the FHH cases. Analysis revealed at least a tendency to pubertal delay in 77% of the CD and in 64% of the FHH families and a diagnosis of delay in 38% of the CD and 44% of the FHH families. Both parents contributed to the positive family histories. The rates of positive family histories among the CD and FHH groups were approximately twice those seen among the other subjects in our case series. Among all subjects, those with FHH had the most marked growth delay, and girls had the greater bone age delay. Among the boys and at comparable chronological ages, CD and FHH were characterized by greater delays in pubic hair development and bone age than in the other diagnostic groups. Although CD is typically associated with leanness, 22% of our subjects had a BMI SD score at the 85th percentile or above for chronological age. These overweight subjects differed from the rest of the CD group: bone age was less delayed, and height was less affected. Finally, our analysis suggested a possible association between attention deficit disorder with or without hyperactivity and pubertal delay in our CD and FHH subjects. Our study provides valuable data regarding the variety and frequency of diagnoses that lead to delayed puberty. The results underscore the importance of performing a thorough evaluation and family history in adolescents with delayed puberty. Moreover, the data from our case series provide clues for unraveling the mechanism(s) of idiopathic pubertal delay and lead to the hypothesis that the pubertal delay seen among some subjects with FHH and CD may stem in part from similar underlying physiology.